Because of high incidence of cigarette smoking among depressed individuals, it has been postulated that smoking may reflect an attempt at self-medication with nicotine by these individuals. We have observed anti-depressant effects of nicotine in an animal model of depression. Moreover, the effects of nicotine can be blocked by pre-administration of the nicotine antagonist, mecamylamine. There is also a differential expression of nicotinic receptors in depressed rat lines compared to their controls. These findings suggest a role for nicotinic receptors in depressed rat lines compared to their controls. These findings suggest a role for nicotinic receptors in depressive characteristics of animals. Nicotinic receptors are potent modulators of a variety of neurotransmitters including biogenic amines which have been directly implicated in human depression.. Although nicotinic manipulation may constitute a novel intervention in depressive disorders, a clearer understanding of the role of specific nicotinic receptors in depression is critical in developing pharmacotherapies for this devastating mental disorder. Here, we hypothesize that depression is associated with inherent changes in specific nicotinic and/or biogenic amine pathways. Furthermore, we postulate that nicotine would tend to normalize these neurotransmitter systems. These hypotheses will be tested in two rat models of depression by examining the role of nicotinic receptor subtypes as well as the contribution of selective dopaminergic noradrenergic and serotonergic pathways to depressive characteristics in these animals. Specifically, we will: 1) determine the effects of selective noradrenergic and serotonergic neurons in selective pathways implicated in mood regulation; 3) determine the basal function of biogenic amines in selective pathways; 4) determine the effects of nicotine functionality of these pathways; 5) determine central and peripheral bioavailability of nicotine. Behavioral analysis will include measurements of several parameters in the forced swim test as well as locomotor activity. Neuronal densities will be assessed by stereological technique. In-vivo microdialysis will be used to determine the functionality of the neurotransmitter systems. Plasma and brain nicotine and cotinine levels will be measured by gas chromatograph-mass spectrometry. The information provided by these studies will significantly advanced our understanding of biological substrates of depression and can lead to novel pharmacotherapies for this disorder.